Lower IgG somatic hypermutation rates during acute dengue virus infection is compatible with a germinal center-independent B cell response

Abstract

BackgroundThe study of human B cell response to dengue virus (DENV) infection is critical to understand serotype-specific protection and the cross-reactive sub-neutralizing response. Whereas the first is beneficial and thus represents the ultimate goal of vaccination, the latter has been implicated in the development of severe disease, which occurs in a small, albeit significant, fraction of secondary DENV infections. Both primary and secondary infections are associated with the production of poly-reactive and cross-reactive IgG antibodies.MethodsTo gain insight into the effect of DENV infection on the B cell repertoire, we used VH region high-throughput cDNA sequencing of the peripheral blood IgG B cell compartment of 19 individuals during the acute phase of infection. For 11 individuals, a second sample obtained 6 months later was analyzed for comparison. Probabilities of sequencing antibody secreting cells or memory B cells were estimated using second-order Monte Carlo simulation.ResultsWe found that in acute disease there is an increase in IgG B cell diversity and changes in the relative use of segments IGHV1-2, IGHV1-18, and IGHV1-69. Somewhat unexpectedly, an overall low proportion of somatic hypermutated antibody genes was observed during the acute phase plasmablasts, particularly in secondary infections and those cases with more severe disease.ConclusionsOur data are consistent with an innate-like antiviral recognition system mediated by B cells using defined germ-line coded B cell receptors, which could provide a rapid germinal center-independent antibody response during the early phase of infection. A model describing concurrent T-dependent and T-independent B cell responses in the context of DENV infection is proposed, which incorporates the selection of B cells using hypomutated IGHV segments and their potential role in poly/cross-reactivity. Its formal demonstration could lead to a definition of its potential implication in antibody-dependent enhancement, and may contribute to rational vaccine development efforts.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0276-1) contains supplementary material, which is available to authorized users.

Development of a potent and protective germline-like antibody lineage against Zika virus in a convalescent human

“…For the overall B cell response, plasmablast-derived antibodies from ZIKV-infected, DENV-naïve donor showed low levels of SHM, supporting the mechanism of naïve B cell activation [19]. Lower IgG somatic hypermutation rates also reported during acute DENV infection, which is consistent with an innate-like antiviral recognition mediated by B cells using defined germline-coded B cell receptors [52]. Therefore, the inducing of germline-coded neutralizing antibodies occupies critical positon in the B cell response during acute flavivirus infection.…”

Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors

“…1D). A bias toward VH1–69 has also been observed in anti-HIV-1, anti-influenza, and anti-HCV repertoires (34–36), and recent studies have shown that there is a significant increase in the relative usage of VH1–18, VH1–2, and VH1–69 during acute dengue infection (37). Hence, it appears that these particular germline gene segments may have inherent properties that facilitate recognition of viral envelope proteins.…”

Development of a Potent and Protective Germline-Like Antibody Lineage Against Zika Virus in a Convalescent Human

“…For the overall B cell response, plasmablast-derived antibodies from a ZIKV-infected, DENV-naïve donor showed low levels of SHM, supporting the mechanism of naïve B cell activation (19). Low levels of IgG SHM were also reported during acute DENV infection, which is consistent with an "innate-like" antiviral recognition mediated by B cells possessing antigenspecific naïve B cell receptors (54). Therefore, the induction of germline-encoded neutralizing antibodies is critical for effective protection against acute flavivirus infection.…”